The recent increase in GWAS discovery power for psychiatric disorders has led to the recognition of an undisputed genetic basis for schizophrenia (SZ). However, the mechanistic basis of the vast majority of these loci remains uncharacterized, hindering the ability to translate genetic findings into novel drug targets and develop new treatments for SZ patients. In this proposal, we overcome these challenges and seek to identify and characterize novel SZ driver genes and causal variants by combining computational and experimental methods, integrating systems-level information to prioritize individual genes and loci, and validating their gene- regulatory and cellular effects in 10 neuronal and 3 glial cell tyes derived from iPS cells. Aim 1: We infer gene co-expression networks and modules using multiple brain regions and developmental stages, and use them to predict schizophrenia driver genes based on their clustering in common networks/modules, and their linking to schizophrenia-associated loci using activity correlation, chromatin conformation and eQTLs. Aim 2: We search for schizophrenia-enriched modules of enhancer regions, discovered by clustering patterns of H3K27ac activity across brain regions, developmental stages, and individuals, using an iterative probabilistic framework for joint prediction of causal driver genes, variants, and regulators. Aim 3: We experimentally validate the gene- regulatory and neuronal/glial cellular phenotypes of predicted schizophrenia driver genes and variants in neuronal and glial cell lines based on targeted sequencing of heterozygous loci overlapping 800 putative driver genes and 10,000 putative causal variants, and systematic profiling of neuronal and glial phenotypes upon knockdown and knockout of 200 candidate genes and bidirectional CRISPR-Cas9 editing of 50 candidate causal variants. If successful, this ambitious proposal has the potential to reveal dozens of new target genes and variants associated with Schizophrenia, and open up new avenues for therapeutic development that may alleviate the personal and societal burden of schizophrenia in our lifetimes.